Introduction

The selection and implementation of appropriate treatments for locally advanced prostate cancer are probably the most difficult challenges which face the physician and his or her patients. If making good decisions is difficult in the treatment of localized prostate cancer and advanced prostate cancer, then making good decisions in the treatment of locally advanced disease can only be described as nerve-racking!

Patients need to understand up front that there are absolutely no "right answers" in the treatment of locally advanced disease. The wise patient, while taking an optimistic approach, may wish to consider the following simple realities:

Once prostate cancer has clearly escaped the confines of the prostate,
the chances that it is truly curable become very small given currently
available forms of treatment. (It is everyone's goal to change this in the
near future.)

Despite the fact that locally advanced disease is not usually curable,
current forms of therapy
can offer long-term remissions (of 10 or even 20 years) to a very
high proportion of
patients if they receive suitable and early intervention.

Many patients who are initially advised by their physicians that they
have locally advanced disease are
found to have micrometastases (and therefore advanced disease) at a later
date. In other words, what may initially appear to be locally advanced
disease can commonly be seen, in retrospect, to have been advanced disease.
This is no one's fault. We simply do not have the diagnostic tools
available today
to be able to specifically identify patients with micrometastatic advanced
disease.

The Prostate Cancer InfoLink recognizes that this information is not,
by any manner of thinking, the information which a newly diagnosed patient
with locally advanced prostate cancer wants to hear. However, over time
such patients
will, we hope, discover that the best treatment decisions tend to be made by
patients who can work with their physicians because both parties are
fully aware of the facts surrounding their situation. We hope that in time
we may be forgiven by those patients who initially react by seeing us as
the bringers of news they would have preferred not to hear, and that at
least some patients will be able to make better treatment decisions because
of their early recognition and acceptance of this situation.

Defining locally advanced disease

There are several types of locally advanced prostate cancer, and we will take the
time to itemize them here for clarity. This set of definitions will require
the reader to have a good appreciation of the "staging" systems used to
discuss prostate cancer. If you have not already read the section on
clinical staging of prostate cancer, you are
strongly advised to now!

Unilateral and bilateral extracapsular extension

Prostate cancer can grow through the capsule (the wall of the prostate) and
into the surrounding tissues. If this has happened from just one lobe of
the prostrate, this is called unilateral extracapsular extension,
which is classified as clinical stage T3/a/Nx/M0. By contrast, if this has
happened from both lobes of the prostate, it is known as bilateral
extracapsular extension and is classified as clinical stage T3b/Mx/M0.
(Note: The use of Nx means that no determination has
been made as to whether the disease has spread to the pelvic lymph nodes.)

Seminal vesicle-positive disease

The seminal vesicles are attached to the prostate (see
Where is your prostate and what does it do?).
It is common
for prostate cancer to spread from the prostate into the seminal vesicles.
Spread of prostate cancer from the confines of the prostate into the seminal
vesicles is a second form of locally advanced prostate cancer. Regardless of
whether the disease has spread into just one of the two seminal vesicles
or into both seminal vesicles, it is classified as stage
T3c/Nx/M0 disease.

Tumor fixed to or invading adjacent structures

If the tumor has escaped from the prostate capsule and it has become
attached to or has infiltrated other nearby parts of the pelvic area other
than the seminal vesicles, then it is classified slightly differently.

If the tumor escapes the prostate and invades the bladder neck, or the
external sphincter, or the rectum, then it is classified as clinical stage
T4a/Nx/M0. Similarly, if the tumor escapes the prostate and invades the
levator ani muscles or the pelvic wall itself, then it is classified as
clinical stage T4b/Nx/M0.

Lymph-node positive disease

The final category of locally advanced prostate cancer is when the patient is
found to have prostate cancer cells in his pelvic lymph nodes. In this case his
disease is generally classified as either T3/N+/M0 disease or
T4/N+/M0 disease, depending on whether he has T3 or T4 disease. In addition,
the degree of lymph node invasion allows for subclassification as follows:

N1 = metastasis in a single lymph node (2 cm or less in greatest
dimension)

N2 = either metastasis in a single lymph node (2-5 cm in greatest
dimension) or multiple lymph node metastases (none more than 5 cm in
greatest dimension)

Pete M. is initially diagnosed with locally advanced prostate cancer on the
basis of his DRE, his PSA test, his biopsy results (which included a biopsy of his seminal
vesicles) and a bone scan. The PSA was 43 ng/ml; the DRE was negative; the
biopsy was positive in four of six cores and in one seminal vesicle; the bone scan
was negative. The preliminary clinical stage was given as T3c/Nx/M0. However,
before they decided on treatment, Pete and his physician decided to carry out
a laparoscopic lymphadenectomy. Pete's physician was just sufficiently concerned
about his PSA level in combination with the positive seminal vesicle that
he suspected a high risk of positive lymph nodes. He was correct, Pete had
small foci of metastasis (both smaller than 1 cm) in two pelvic lymph nodes.
He was restaged as T3/N2/M0.

Jerry B. is also initially diagnosed with locally advanced prostate cancer.
He has a positive DRE with apparent extracapsular penetration through both lobes of the
prostate. His PSA value is 14.7 ng/ml. His seminal vesicles are negative on
biopsy and his bone scan is negative. He is tentatively staged as T3-4/Nx/M0.
His urologist is uncertain as to the extent of local extracapsular disease
and whether Jerry may have positive lymph nodes. However, because the urologist
considers radical prostatectomy to be inappropriate for Jerry, no attempt is
made to evaluate his lymph node status by the use of a laparoscopic
lymphadenectomy.

The treatment options: an introduction

The Prostate Cancer InfoLink will gradually expand to offer detailed commentary on the
differing options for the treatment of the various types of locally
advanced prostate cancer. At this point in time, patients are advised
simply that there are a wide range of options and that the selection of
the appropriate option for an individual patient is perhaps as much an art as it
is a science.

The general rule of thumb should be that the more advanced the disease, the
less likely it is that purely surgical or purely radiotherapeutic
interventions will succeed in controlling
the disease. Indeed, there are now few surgeons who would consider that
surgical intervention without some form of neoadjuvant or adjuvant therapy
is appropriate for the management of most forms of locally advanced disease.
Equally, the radio-oncology community now seems to accept that radiotherapy
is much more likely to succeed in offering long-term progression-free
survival if it is combined with hormonal manipulation of some form.

Basically, the list of possible categories of treatment is as follows:

Radical prostatectomy alone, which is probably only even
potentially appropriate today in patients who are suspected of
seminal vesicle involvement but in whom one or more attempts to biopsy the seminal
vesicles were negative

Radiation therapy alone, carried out using external beam radiation
or brachytherapy or a combination of the two (and it should be noted that
external beam radiotherapy alone is now stated by at least
some highly regarded experts on the radiotherapy of prostate cancer to be "inadequate")

Neoadjuvant hormone therapy followed by radical prostatectomy,
with or without adjuvant (post-surgical) hormone therapy

Neoadjuvant hormone therapy followed by radiation therapy,
with or without adjuvant (post-surgical) hormone therapy

Neoadjuvant hormone therapy followed by cryotherapy, with or
without adjuvant (post-surgical) hormone therapy.

It can be seen from this extensive list just how complex the treatment options
for management of locally advanced disease can be. When one starts to consider
all of the various categories of adjuvant and neoadjuvant hormonal manipulation
that are now either available or in clinical trials, the number of options
becomes difficult to assess on a purely scientific basis.

Lymph node positive or lymph node negative?

The question whether the cancer has reached the lymph nodes is one of two questions
which are absolutely fundamental to the choice of therapy. Basically, if the cancer
has escaped into the pelvic lymph nodes, surgical treatment alone is no
longer considered to be effective, although surgical treatment in combination
with other forms of therapy may be beneficial.

Patients should be aware, however, that it is common (and very reasonable) for
urologists to attempt surgery in the hope that cancer is confined to the
prostate, but to discover at the beginning of surgery -- using a rapid pathologic
technique known as a "frozen section" -- that in fact the cancer has reached the
lymph nodes. In such cases it is not unusual to terminate the surgical procedure
without removing the prostate and to inform the patient that other forms of
treatment will have to be attempted. All patients who are scheduled for
surgery for prostate cancer will normally be advised of this possibility prior to
surgery -- even patients definitively believed to have localized disease. There is
always at least some risk that the cancer will have progressed to the lymph nodes,
despite every indication to the contrary. This situation is altered by
the use of neoadjuvant and adjuvant hormonal therapy or by the prior
agreement between physician and patient that the prostate will be removed unless,
in the opinion of the surgeon, the degree of lymph node metastasis is so
high as to make removal of the prostate pointless.

If a patient has positive lymph nodes, the value of radiotherapy as a primary
form of treatment is also open to considerable question. As indicated previously, there
are now eminent radio-oncologists who consider that radiotherapy alone is
inappropriate for the treatment of any form of T3 or T4 prostate cancer.
This is surely even more likely to be the case in patients with node-positive
disease.

How did the disease escape the prostate?

Just as this issue of lymph node positivity has significant implications
for the management of individual patients, so does the question of whether
a patient has T3 or T4 disease. In other words, if a patient is seminal vesicle
positive, but otherwise the disease is localized to the prostate capsule,
different treatment options may be appropriate than if the patient has clear
signs that the cancer has escaped through the wall of the prostate and infiltrated
the surrounding pelvic tissues.

Is node-positive disease really locally advanced?

It should be noted that the classification
of node-positive disease as "locally advanced" is open to question. Many experts
would consider that node-positive disease should be classified as
"advanced" or "systemic." In the older Jewett-Whitmore staging system for
prostate cancer, node-positive disease was classified as stage D1 disease.

The Prostate Cancer InfoLink takes the position that there is a distinction
between definitively node-positive disease, in which the cancer has
reached the lymph nodes but has not metastasized beyond these nodes
(i.e., true T3-4/N+/M0 disease), and
true micrometastatic disease, in which the cancer has really has
micrometastasized
beyond the lymph nodes but is not clearly identifiable as stage M+. The problem,
of course, is that in most cases we are currently unable to distinguish between
these two situations.

The Prostate Cancer InfoLink would simply note that just because we cannot yet distinguish between
these two clinical situations does not alter the fact that the former
situation can be clearly seen as locally
advanced (because the disease is still confined to the pelvis, and is therefore
theoretically amenable to localized therapy), whereas the latter situation
is clearly systemic. We would suggest that it time management decisions
will be able to take account of this distinction, and that therefore
we should take it into account in our thinking.

Concluding remarks

The information offered here should be seen only as a series of introductory
remarks on the options available to physician and patient for the management
of locally advanced disease.

Over the forthcoming weeks, we hope to develop a series of detailed commentaries
on the information available regarding the different types of treatment
identified earlier in this section.

The content in this section of the Phoenix 5 site was originally developed by CoMed Communications (a Vox Medica company) as part of The Prostate Cancer InfoLink. It is reproduced here with the permission of Vox Medica.